Chemical compounds



United States Patent 3,356,683 CHEMICAL COMPOUNDS Jack Bernstein andKathryn A. Losee, New Brunswick, N.J., assignors, by mesne assignments,to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of DelawareNo Drawing. Filed June 3, 1965, Ser. No. 461,193 4 Claims. (Cl. 260295)This invention relates to new chemical compounds and more particularlyto mixed anhydrides of l-hydroxy-Z (1H)-pyridones and carboxylic acids.

The preferred compounds of this invention are those of the generalformula wherein R is an organic radical of less than twelve carbonatoms, R is hydrogen, lower alkyl, lower alkoxy, phenyl- (lower alkoxy),nitro, or-halogen, m is a positive integer less than five (preferablyone), it is zero or one, X is oxygen or sulfur, and R is hydrogen orlower alkyl. Suitable values for R include: lower alkyl (e g., methyl,ethyl, propyl, butyl, pentyl and n-hexyl); lower alkenyl (e.g., vinyl,allyl, isopropenyl, butenyl, pentenyl and hexenyl); lower alkadienyl(e.g., pentadienyl); lower akynyl (e.g., ethynyl and propynyl); phenyl;naphthyl; lower alkyl, lower alkoxy, nitro, trifiuoromethyl or halosubstituted phenyl; and lower alkyi, lower alkoxy, nitro,trifiuoromethyl, or halo substituted naphthyl.

The compounds are prepared by the processes of this invention, one ofwhich essentially comprises interacting a 1-hydroxy-2(lH)-pyridone ofthe formula wherein R and m are as hereinbefore defined, with an acylhalide of the formula: RCO(halo), wherein R is as hereinbefore defined.Those compounds wherein n is one are prepared by the second process ofthis invention which comprises reacting a 1-hydroxy-2(1H)-pyridone ofthe formula given hereinbefore, with an isocyanate or thioisocyanate ofthe formula: RNCX, wherein R and X are hereinbefore defined, or with acarbanyl chloride of the formula:

R-NC-lialo wherein R, R and X are as hereinbefore defined.

The compounds of this invention are physiologically active substancesthat possess antibacterial activity when administered topically.

The following examples illustrate the invention (all temperatures beingin centigrade):

EXAMPLE 1 Anhydriae of 1-hydr0xy-2(1H)-pyrid0ne and benzoic acid 11.1 g.of 1-hydroxy-2(1H)-pyridone and 10.1 g. of N- methyl-morpholine aredissolved in 250 cc. of dry chloroform and 14 g. of benzoyl chloride areadded dropwise at There is a temperature rise to 36. After completeaddition, the mixture is refluxed for two hours, cooled and the solventremoved under reduced pressure. The residue is triturated with ether andthe insoluble solid filtered. This solid is triturated with water andfiltered to yield about 10 g. the anhydride of 1-hydroxy-2(1H)-pyridoneand benzoic acid, M.P. about 140142. After recrystallization frombenzene the compound melts at about 140 142.

Analysis.-Calcd. for C H NO N, 6.51; C, 66.97; H, 4.21. Found: N, 6.43;C, 66.93; H, 4.22.

EXAMPLE 2 Anhydride 0f J-hya'roxy-Z(1H)-pyrid0ne and methylcarbamic acid11.1 g. of 1-hydroxy-2(1H)-pyridone is suspended in 150 cc. ofchloroform and 5.7 g. of methyl isocyanate in 50 cc. of chloroform isadded dropwiseat 22 over a period of one-half hour. There is atemperature rise to 27 and a dark brown solution forms. This is refluxedfor one hour, cooled and the solvent removed under reduced pressure toyield about 18 g. of solid anhydride of l-hydroxy- 2(1H)-pyridone andmethylcarbamic acid, M.P. about 140442". This is recrystallized from 300cc. of ethyl acetate to yield about 7 g. of product, M.P. about 148-Recrystallization from 300 cc. of ethyl acetate yields about 3.6 g. ofpure product melting at about 149-151.

Analysis.Calcd. for C I-I N O C, 49.99; N, 16.66; H, 4.78. Found: C,50.14; N, 16.80; H, 5.12.

. EXAMPLE 3.

Anhydride of J-hydroxy-Z(1H)-pyridone and acetic acid Following theprocedure of Example 1, but substituting an equivalent amount of acetylchloride for the benzoyl chloride, the anhydride of1-hydroxy-2(1H)-pyridone and acetic acid is formed.

EXAMPLE 4 Anhydride of 1-hydroxy-4-methyl-2(1H)-pyrid0nc and benzoicacid Following the procedure of Example 1, but substituting anequivalent amount of 1-hydroxy-4-methyl-2(1H)-pyridone for the1-hydroxy-2(1H)-pyridone, the anhydride of1-hydroxy-4-methy1-2(1H)-pyridone and benzoic acid is obtained.

EXAMPLE 5 Anhydride 0f 1-hydr0xy-5-br0mo-2(1H)-pyrid0ne and benzoic acidFollowing the procedure of Example 1, but substituting an equivalentamount of 1-hydroxy-5-bromo-2(1H)-pyridone for the1-hydroxy-2(1H)-pyridone, the anhydride of1-hydroxy-5-bromo-2(lH)-pyridone and benzoic acid is obtained.

EXAMPLE 6 Anhydride of 1-hydroxy-6-br0m0-2(1H)-pyrid0ne and acrylic acidFollowing the procedure of Example 1, but substituting an equivalentamount of 1-hydroxy-6-bromo-2(1H)- pyridone for the1-hydroxy-2(1H)-pyridone and an equiva- 3 lent amount of acrylylchloride for the benzoyl chloride, the anhydride of1-hydroxy-6-bromo-2(1H)-pyridone and acrylic acid is obtained.

EXAMPLE 7 Anhydride of l-hydroxy-Z (1H) -pyridne and phenylcarbamic acidFollowing the procedure of Example 2, but substituting an equivalentamount of phenylisocyanate for the methylisocyanate, the anhydride of 1hydroxy 2(1l-I)- pyridone and phenylcarbamic acid is obtained.

EXAMPLE 8 Anhydride of l-hydroxy-Z(1H)-pyrid0ne and phenyldithiocarbamicacid Following the procedure of Example 2, but substituting anequivalent amount of phenylisothiocyanate for the methylisocyanate, theanhydride of 1-hydroxy-2(1H)- pyridone and phenyldithiocarbamic acid isobtained.

EXAMPLE 9 Anhydria'e of 1-hydr0xy-2(1 H)-pyrid0ne anddiethyldithiocarbamic acid Following the procedure of Example 1, butsubstituting an equivalent amount of diethylthiocarbamyl chloride forthe benzoyl chloride, the anhydride of l-hydroxy-Z (1H)-pyri'done anddiethyldithiocarbamic acid is formed.

EXAMPLE 10 Anhydride of J-hydroxy-Z(MD-pyridone and N-methyl-N(m-tolyl)-dirhi0carbamic acid 4 What is claimed is: 1. An anhydride ofthe formula wherein n represents 0 or 1; R, when n represents 0, isselected from the group consisting of lower alkadienyl, lower alkynyl,phenyl and lower alkyl-phenyl; R, when n represents 1, is selected fromthe group consisting of lower alkyl, phenyl and m-tolyl; R is selectedfrom the group consisting of hydrogen, lower alkyl and halogen; m is 0or 1; X is selected from the group consisting of oxygen and sulfur and Ris selected fromthe group con sisting of hydrogen and lower alkyl.

2. A compound in accordance with claim 1 having the name1-benzoyloxy-2(H)-pyridone.

3. A compound in accordance with claim 1 wherein n is 1 and R istloweralkyl.

4. A compound in accordance with claim 3 having the name1-methylcarbamyloxy-2(lH)-pyridone.

References Cited UNITED STATES PATENTS 9/1960 Pullen et a1. 16730 OTHERREFERENCES WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

A. L. ROTMAN, Assistant Examiner.

1. AN ANHYDRIDE OF THE FORMULA